It is well known that many drugs taken orally, are destroyed on the first pass through the liver. It is also well known that when many drugs are taken orally, their rate of absorption into the body is not constant. In view of such difficulties, a number of different drug delivery systems have been developed. Recently, the use of transdermal delivery systems have met with increasing interest by researchers in the pharmaceutical drug delivery field.
U.S. Pat. No. 4,291,015 to Keith, et al., discloses the use of a polymeric diffusion matrix for the sustained release of pharmaceutically active drugs. The matrix is covered by a backing layer and applied to the skin where diffusion of the pharmaceutically active drug occurs and the drug is transdermaley delivered to the patient. Although U.S. Pat. No. 4,291,015 discloses transdermal delivery of nitroglycerine, other drugs may be delivered by utilizing the same or a similar matrix, as disclosed in U.S. Pat. Nos. 4,292,820; 4,292,302; and 4,292,303.
U.S. Pat. No. 4,490,206 discloses the use of a different type of transdermal delivery system whereby the pharmaceutically active drug is dispersed within an adhesive (see also U.S. Pat. No. 4,390,520). In accordance with such systems, the pharmaceutically active drug is dispersed in a pressure-sensitive adhesive which is adhered to the skin. The drug then diffuses from the adhesive through the skin for delivery to the patient. Other types of transdermal delivery systems are also known and each has various advantages and disadvantages with respect to the transdermal delivery of different types of pharmaceutically active drugs.
One of the problems with utilizing transdermal delivery systems is one of efficacy. More specifically, the device must supply a sufficient amount of the pharmaceutically active ingredient to the patient to obtain the desired pharmaceutical effect on the patient over a given period of time. Different means may be employed in order to obtain the desired efficacy over that period of time.
One means of attempting to increase the amount of drug delivery might be to include a higher concentration of the pharmaceutically active drug in the delivery system. By simply increasing the concentration of the drug, the amount of the drug delivered to the patient would hopefully be increased. This concept might work well to a certain extent but would be limited by the amount of drug which can be delivered through the skin barrier, i.e., the skin acts as a rate limitation means.
Another means for increasing the amount of drug delivered and obtaining the desired efficacy, might involve increasing the surface area contact of the delivery system with the skin. Although an increase in the surface area will increase the amount of drug delivered to the patient, there are, of course, practical limitations with respect to increasing this surface area. The cost of producing very large delivery systems might be prohibitive. Patients would be unlikely to ware a delivery system which had a surface such that it covered the entire back and/or front of the patient.
A completely different concept for increasing transdermal delivery of a pharmaceutically active drug is the utilization of a penetration enhancer to be used in combination with the drug delivery system. Utilization of such enhancers is subject to certain limitations such as the fact that the enhancer must be determatologically acceptable, and compatible with the pharmaceutically active drug as well as the delivery system which it is used in connection with.
Perhaps the most famous of such penetration enhancers is "DMSO (Dimethyl sulfoxide)". However, DMSO has not received FDA approval for use on humans. Another well known penetration enhancer is AZONE, see U.S. Pat. Nos. 3,909,816; 4,311,481; and 4,316,893 as well as the corresponding foreign patents.
More recently, there has been some teachings with respect to the use of oleic acid as a penetration enhancer. (See Cooper, Eugene, R., "Increased Skin Permeability for LITOTHILIC Molecules" Journal of Pharmaceutical Sciences, volume 73, number 8, August 1984.) Cooper discloses the use of oleic acid in different concentrations in the presence of propylene glycol as a solid. The oleic acid does appear to enhance penetration of the active ingredient SALICYLIC acid. Cooper also discloses the use of oleic acid in combination with 1,2-butanediol. The article specifically indicates that "other diols also exhibit this synergism with lipids, but the effect is less pronounced as the chain length is increased". Cooper teaches that the treatment of the skin with surfactants can have a substantial influence on increasing the penetration of polar molecules. However, such surfactants do not generally increase the transdermal penetration of the non-polar molecules. Accordingly, Cooper concludes that the enhanced transdermal penetration of non-polar molecules such as salicylic acid can be obtained by the addition of small amounts of fatty acids or alcohols to the formulation. More specifically transdermal penetration of salicylic acid can be greatly enhanced by the addition of small amounts of oleic acid. Accordingly, Cooper appears to teach only the use of small amounts of oleic acid either alone or in combination with diols of short chain length and contains no teachings with respect to the use of large amounts of oleic acid alone or in combination with long chain diols and actually teaches against the use of such long chain diols.
U.S. Pat. No. 4,305,936 discloses a solution for topical or local application comprised of a corticosteroid in a carrier. The carrier is comprised of 1 to 4% by weight of solubilizing agents of a glyceral ester of a fatty acid containing 6 to 22 carbon atoms, 10 to 50% by weight of an alkanol cosolvent and from 20 to 50% by weight of water. The patent also indicates that the carrier can include a carrier a "suitable auxiliary adjuvant in an amount of up to 10% by weight." Oleic acid is mentioned as a suitable auxiliary adjuvant. The patent does not appear to contain any teaching with respect to the effect oleic acid might have on enhancing penetration and does not appear to contain any teachings with respect to the use of large amounts of oleic acid alone or in combination with a long chain diol.
U.S. Pat. No. 4,455,146 discloses a plaster comprised of a thermalplastic elastomer, an oil or higher fatty acid, a tack-providing resin and an active ingredient. The "higher fatty acid" may be present in the range of 25 to 370 parts by weight per 100 parts by weight of the thermalplastic elastomer. The active ingredient may be present in an amount in the range of 0.09 to 110 parts by weight per 100 parts by weight of the thermalplastic elastomer, (see column 4, lines 3-35). Oleic acid is mentioned as "one of the preferred" higher fatty acids, (see column 3, lines 16-17).
Although percutaneous penetration enhancers are known, there remains a need for an enhancer which is dermatologically acceptable has FDA approval for use on human skin and has a substantial effect on increasing in the rate of transdermal delivery of a pharmaceutically active drug to a patient.